Investigation of a MMP-2 Activity-Dependent Anchoring Probe for Nuclear Imaging of Cancer

Abstract

PurposeSince matrix metalloproteinase-2 (MMP-2) is an important marker of tumor malignancy, we developed an original drug design strategy, MMP-2 activity dependent anchoring probes (MDAP), for use in MMP-2 activity imaging, and evaluated the usefulness of this probe in in vitro and in vivo experiments.MethodsWe designed and synthesized MDAP1000, MDAP3000, and MDAP5000, which consist of 4 independent moieties: RI unit (111In hydrophilic chelate), MMP-2 substrate unit (short peptide), anchoring unit (alkyl chain), and anchoring inhibition unit (polyethylene glycol (PEGn; where n represents the approximate molecular weight, n = 1000, 3000, and 5000). Probe cleavage was evaluated by chromatography after MMP-2 treatment. Cellular uptake of the probes was then measured. Radioactivity accumulation in tumor xenografts was evaluated after intravenous injection of the probes, and probe cleavage was evaluated in tumor homogenates.ResultsMDAP1000, MDAP3000, and MDAP5000 were cleaved by MMP-2 in a concentration-dependent manner. MDAP3000 pretreated with MMP-2 showed higher accumulation in tumor cells, and was completely blocked by additional treatment with an MMP inhibitor. MDAP3000 exhibited rapid blood clearance and a high tumor accumulation after intravenous injection in a rodent model. Furthermore, pharmacokinetic analysis revealed that MDAP3000 exhibited a considerably slow washout rate from tumors to blood. A certain fraction of cleaved MDAP3000 existed in tumor xenografts in vivo.ConclusionsThe results indicate the possible usefulness of our MDAP strategy for tumor imaging.

A Prodrug-type, MMP-2-targeting Nanoprobe for Tumor Detection and Imaging

“…Among the currently known MMPs, MMP-2 is frequently overexpressed in the majority of solid tumors such as breast, colon and prostate cancers, and its significant role in promoting cancer progression 5 renders it an important target for tumor diagnosis and therapy. 6 - 8 Therefore, development of sensitive detection of MMP-2 offers a great value for tumor monitoring.…”

Nanomaterial Technology and Soft Tissue Sarcomas

“…The overexpression of tumor-associated proteins (TAPs) occurs during tumor formation, and TAPs can regulate proteolysis, making them an important factor in cancer progression. For example, MMP-2 is a TAP overexpressed in most solid tumors including STSs (52), which can be used for the detection of such tumors. Wang et al (53) developed a nanoprobe containing an MMP-2 substrate sequence for detecting MMP-2-overexpressed tumors, which is highly activated in human fibrosarcoma HT1080 cells in vitro and highly expressed in human fibrosarcoma HT1080 cell xenografts compared with MCF-7 cells.…”

“…The overexpression of tumor-associated proteins (TAPs) occurs during tumor formation, and TAPs can regulate proteolysis, making them an important factor in cancer progression. For example, MMP-2 is a TAP overexpressed in most solid tumors including STSs ( 52 ), which can be used for the detection of such tumors. Wang et al.…”

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“…Nuclear medicine imaging studies rely on the production and availability of radiotracers that target disease biomarkers or biological components. A wide range of radiotracers have been developed that target growth factor receptors [5,6], signaling components [7], markers of apoptosis [8], proliferation markers [9], proteolytic enzymes [10], tumor neovasculature [11], extracellular matrix proteins [10], and molecular antigens inside cells [12]. Biomarkers of disease have become increasingly useful in the evaluation of clinical and translational cancer research.…”